Lymphocytes maturing in the thymus (T cells) play an important role in protecting vertebrate organisms from infection. As such, the mature cells must be able to distinguish between healthy and infected self tissue. A major part of the selection of the T cell repertoire for this key discriminating function occurs in the thymus. The clonally-unique antigen receptor (TCR) recognizes products of the major histocompatibility complex (MHC) and their bound peptides. The last several years have demonstrated that two forms of regulated cell death occur in the thymus to regulate repertoire selection. One form of death is prevented by insuring that the TCR has the capacity to recognize self MHC-peptide. This positive selection insures that lymphocytes allowed to mature will be functional rather than filling the lymphoid compartment with non-functional cells that have no capacity to recognize self MHC and therefore no capacity to recognize MHC on cells that are infected with pathogens. The second form of death eliminates those clones whose TCR reacts so strongly with self MHC-peptide that they would become autoimmune effector cells if allowed to mature (clonal deletion). Thus within the thymus, TCR stimulation at one level prevents one form of death while stimulation at a more intense level appears to activate a death pathway. The role of TCR-stimulated death (deletion) in the mature T cell compartment of the periphery has been controversial. It has been argued that such a mechanism should exist to eliminate those T cells that would be autoreactive to cells whose differentiation-specific antigens are physically or temporally absent in the thymus during T cell maturation. However, it is difficult to reconcile the existence of a system of peripheral deletion that retains the capacity to productively respond to an infectious challenge. We have recently found two, mutant "autoimmune" strains of mice that exhibit a defect in a unique peripheral deletion pathway. The autoimmune mice have selectively uncoupled TCR-stimulation from the death pathway in mature T cells. We have also observed in wild- type mice that products on the antigen presenting cell (APC) can selectively uncouple TCR-stimulated suicide from other functions associated with a productive immune response. In this proposal we will examine the molecular basis for coupling T cell death to TCR stimulation in mature T cells and compare T cell responses in wild-type and mutant mice to better understand the biological role of this unique death pathway in peripheral, mature T cells.